2-(5&#39;-nitro-2&#39;-furyl)-thieno(2,3-d)pyridines and salts thereof

ABSTRACT

COMPOUNDS OF THE FORMULA   2-(5-(O2N-)-FUR-2-YL),4-R,5-R1,6-R2-THIENO(2,3-D)PYRIMI   DINE   WHEREIN R IS FREE AMINO; LOWER ALIPHATIC ACYLAMINO OPTIONALLY MONO- OR DI-CHLORO-SUBSTITUTED ON THE ACYL MOIETY; (STRAIGHT OR BRANCHED MONOALKYL OF 1 TO 5 CARBON ATOMS)-AMINO; DI(AKYL OF 1 TO 4 CARBON ATOMS)AMINO, WHERE THE ALKYL MOIETIES MA BE IDENTICAL TO OR DIFFERENT FROM EACH OTHER; MONO- OR DI-HYDROXY (STRAIGHT OR BRANCHED ALKYL OF 1 TO 5 CARBON ATOMS) AMINO, WHERE THE ATOMS SUBSTITUENT ATTACHED AN ALKYL OF 1 TO 4 CARBON ATOMS SUBSTITUENT ATTACHED THERETO; DI-(HYDROXY (STRAIGHT OR BRANCHED ALKYL OF 1 TO 3 CARBON ATOMS) AMINO; ALKOXY OF 1 TO 2 CARBON ATOMS (ALKYL OF 1 TO 3 CARBON ATOMS)AMINO; FREE AMINO (ALKYL OF 1 TO 3 CARBON ATOMS)AMINO; N-ACETYL-(ALKYLENE OF 1 TO 3 CARBON ATOMS)-DIAMINO; PIPERIDINO; OR HYDROXY-PIPERIDINO; AND R1 AND R2 WHICH MAY BE IDENTICAL TO OR DIFFERENT FROM EACH OTHER, ARE EACH HYDROGEN, METHYL OR ETHYL. AND NON-TOXIC, PHARMACOLOGICALLY ACCEPATABLE ACID ADDITION SALTS THEREOF; THE COMPOUNDS AS WELL AS THE SALTS ARE USEFUL AS BACTERICIDES, FUNGICIDES AND TRICHOMONACIDES.

United States PatentOtfice 3,830,813 Patented Aug. 20, 1974 US. Cl. 260-256.5 R 11 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula i 02N*LO/ T -Rz wherein R is free amino; lower aliphatic acylamino ptionally monoor di-chloro-subs-tituted on the acyl moiety; (straight or branched monoalkyl of 1 to carbon atoms)-amino; di(alkyl of l to 4 carbon atoms)amino, where the alkyl moieties may be identical to or dilferent from each other; monoor di-hydroxy (straight or branched alkyl of 1 to 5 carbon atoms) amino, where the amino nitrogen may have an alkyl of 1 to 4 carbon atoms substituent attached thereto; di-[hydroxy (straight or branched alkyl of 1 to 3 carbon atoms)]amino; alkoxy of 1 to 2 carbon atoms (alkyl of 1 to 3 carbon atoms)amino; free amino (alkyl of 1 to 3 carbon atoms)amino; N-acetyl-(alkylene of 1 to 3 carbon atoms)-diamino; piperidino; or hydroxy-piperidino; and

R and R which may be identical to or different from each other, are each hydrogen, methyl or ethyl,

and non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as the salts are useful as bactericides, fungicides and trichomonacides.

This invention relates to novel 2-(5'-nitro-2'-furyl)- thieno[2,3-d]pyrimidines and acid addition salts thereof, as well as to various methods of preparing these compounds.

More particularly, the present invention relates to a novel class of 2-(nitro-furyl)-thieno[2,3-d]pyrimidines of the formula oNl i /N S R 2 T i N\/ Br wherein R is free amino; lower aliphatic acylamino optionally monoor di-chloro-substitnted on the acyl moiety; (straight or branched monoalkyl of 1 to 5 carbon atoms)-amino; di(alkyl of 1 to 4 carbon atoms)amino, where the alkyl moieties may be identical to or different from each other; monoor di-hydroxy (straight or branched alkyl of 1 to 5 carbon atoms) amino, where the amino nitrogen may have an alkyl of 1 to 4 carbon atoms substituent attached thereto; di-[hydroxy (straight or branched alkyl of 1 to 3 carbon atoms)]amino; alkoxy of 1 to 2 carbon atoms (alkyl of 1 to 3 carbon atoms) amino; free amino (alkyl of 1 to 3 carbon atoms) amino; N-

a'cetyl-(alkylene of 1 to 3 carbon atoms)-diamino; piperidino; or hydroxypiperidino; and

R and R which may be identical to or different from each other, are each hydrogen, methyl or ethyl;

and non-toxic, pharmacologically acceptable acid addition salts thereof.

The compounds embraced by formula I may be prepared by the following methods:

Method A h mn.

wherein R and R have the same meanings as in formula I, and Z is halogen or free or substituted mercapto,

with an amine of the formula R'-H (III) wherein R has the same meanings as R in formula I except monoor di-chloro-substituted lower aliphatic acylamino.

The reaction is preferably performed in an inert organic solvent or suspension medium at a temperature between 20 and C., and in those instances where Z in formula II is halogen the presence of a hydrogen halidebinding agent is required.

The hydrogen halide-binding agent may be an equimolar amount of an inorganic or tertiary organic base or a molar excess of the amine of the formula III.

The reaction is most advantageously performed in a polar organic solvent medium, such as an alkanol, dimethyl formamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone or hexamethylphosphoric acid triamide.

If it is desired to prepare by this method a compound of the formula I wherein R is free amino(alkyl of 1 to 3 carbon atoms)amino, it is more advantageous to react a compound of the formula II with an amine of the formula III in which R is N-acyl-(alkylene of 1 to 3 carbon atoms)-diamine and subsequently split off the N- acyl substituent of the reaction product by acid hydrolysis.

Method B By reacting a 2-(2'-furyl)-thieno[2,3-d]pyrimidine of the formula l N s Ur If .v

N It; "(no wherein R, R and R have the same meanings as in formula I, with a nitrating agent, such as nitric acid, a mixture of nitric acid and sulfuric acid, or a mixture of nitric acid and acetanhydride. I

In those instances where the substituent R of the starting compound of the formula IV comprises one or mnrefreehdroxyl or amino groups, these groups are provided by conventional methods with suitable protective substituents, such as acyl, prior to the reaction with the nitrating agent. After completion of the nitration reaction the protective substituents may be split oif again by conventional methods, such as by acid hydrolysis.

The nitration reaction generally requires reaction temperatures of to 30 C., and in some instances it is advantageously performed in an inert solvent or diluent.

'Method C 13y reacting a 2- ('-bromo-2-furyl)-thieno[2,3-d1pyrimidine of the formula I s n:

Method D By reacting a 2-=(5'-carboxy-2-furyl)-thieno[2,3-d] pyrimidine of the formula HOOC- L I /N S R R1 II (VI) wherein R, R and R have the same meanings as in formula I, with nitric acid or a salt of nitric acid in the presence of a strong mineral acid, such as concentrated sulfuric acid, at a temperature between 20 and +50 C., preferably from 0 to +20 C.

The mineral acid is advantageously provided in an amount such that it simultaneously serves as the solvent medium for the reaction.

Examples of suitable salts of nitric acid are alakli metal or alkaline earth metal nitrates.

In those instances where substituent R in formula VI comprises free amino or hydroxyl groups, these are proyidedin conventional manner with protectivesubstituents, such as acyl, prior to the nitration reaction; after completion of the reaction the protective groups may, if desired, be split off again by conventional methods, such as by acid hydrolysis.

Method For the prepaartion of a compound of the formula I wherein R is acylamino or monoor di-chloro-substituted acylamino, by acylating a 2j(5'-nitro-2-furyl)-4-aminothino[2,3-d]pyrimidine of the formula (VII) wherein R and R have the same meanings as ,in formula I, with a conventional acylating agent, such as an acid halide or an acid anhydride, at a temperature up to the boiling point of the particular acylating agent which is employed.

The starting compounds required for methods A to E are either known compounds or may be prepared by known methods.

Thus, the starting compounds of the formula II wherein Z is halogen may be prepared by reacting a S-nitrofuran-Z-iminocarboxylic acid ester [see W. R. Sherman et al., J. Med. Chem. 8, 25 (1965)] with a Z-aminothiophene-3-carboxylic acid ester [see K. Gewald, Chem. Ber. 98, 3571 (1965); and ibid, 99, 94 (1966)], followed by halogenation of the intermediately formed 2-(5'-nitro2'- furyl)-4-hydroxy-thieno[2,3-d]pyrimidine with a conventional halogenating agent, such as a phosphorus oxyhalide, phosphorus pentahalide or thionyl halide.

The compounds of the formula II wherein Z is free or substituted mercapto may, for example, be prepared by reacting a corresponding 4-halosubstituted thieno[2,3-d] pyrimidine with thiourea, followed by optional alkylation of resulting 4-mercapto compound with an alkyl halide.

The starting compounds of the formula IV may be prepared by reacting a furan-Z-imino-carboxylic acid ester [see A. Pinner, Chem. Ber. 25, 1416 (1892)] with a 2 aminothiophene-3-carboxylic acid ester to form the corresponding 2- (2'-furyl -4-hydroxy-thieno [2,3-d] pyrimidine, halogenating the latter with a conventional halogenating agent, such as a phosphorus oxyhalide, and reacting the intermediately formed corresponding 2-(2'-furyl)-4 -halothieno[2,3-d]pyrimidine with an amine of the formula RH, where R has the meanings defined in connection with formula I. v

The starting compounds of the formula V may, for instance, be obtained by treating a corresponding 2-(2- furyl)-4-halo-thieno[2,3-d] pyrimidine with a stoichiornetric amount of bromine, and reacting the resulting 2-(5'- bromo-2'-furyl)-4-halo-thieno[2,3-d]pyrimidine with an amine of the formula RH, where R has the same meanings as in formula I. The bromination reaction is preferably performed in an organic solvent medium and in the presence of a hydrogen halide-binding agent at a temperature between 0 and 30 C. Suitable organic solvent media are inert solvents, such as 1,2-dichloroethane, as well as polar solvents, such as glacial acetioacid. An example of a suitable hydrogen halide-binding agent is anhydrous sodium acetate. The subsequent reaction with the amine RH is performed at elevated temperatures, and the amine is preferably provided in sufficient excess over the stoichiometrically required amount to serve simultaneously as the hydrogen halide-binding agent and the solvent medium for the reaction.

The starting compounds of the formula VI may be prepared by reacting a S-carbalkoxy-furan-Z-iminocarboxylic acid ester with a 2-amino-thiophene-3-carboxylic acid ester, halogenating the intermediate thus obtained with a halogenating agent, such as a phosphorus oxyhalide, reacting the halogenation product with an amine of the formula RH, where R has the same meanings as in formula I, and hydrolizing the reaction product in the presence of an acid, such as hydrochloric acid.

Finally, the starting compounds of the formula VII-are obtained by reacting a compound of the formula II with ammonia.

The end products of the formula I obtained by methods A through E are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid, adipic acid, maleic acid, citric acid, 8-chlorotheophylline or the like.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below:

Preparation of Starting Compounds 7 EXAMPLE A 2-(5-Nitro-2-furyl) 4-hydroxy-thieno[2,3-d]pyrimidine A mixture consisting of 18.4 gm. (0.1 mol) of S-nitrofuran-2-iminocarboxylic acid methyl ester, 15.7 gm. (0.1 mol) .of 2-amino-thiophene-3-carboxylic acid methyl ester and 50 ml. of xylene was heated to reflux temperature. After about two hours crystals began to separate out of the clear solution, and after a reaction period of 20 hours the reaction mixture was cooled, the precipitate formed thereby was collected by vacuum filtration, and the filter cake was washed with ether and recrystallized from dimethylformamide, yielding 10.4gm. (40% of theory) of 2-(5'- nitro-2-f-uryl) 4 hydroxy thieno[2,3-d]pyrimidine, m.p. 300 C.

AnaIysis.C H N O S: mol. wt. 263.24: Calculated (percent): C, 45.62; H, 1.92; N, 15.97. Found (percent): C, 45.68; H, 1.97; N, 15.88.

In analogous manner the following compounds were prepared:

(a) 5-Methyl-2-(5'-nitro 2' furyl)-4-hydroxy-thieno- [2,3-d]pyrimidine, m.p. 300 C. (from dimethylformamide), from S-nitrQ-furan-Z-iminocarboxylic acid ethyl ester and 2-amino-4-methyl-thiophene-3-carboxylic acid methyl ester. v

. (b) 6-Methyl 2 (5-nitro-2'-furyl)-4-hydroxy-thieno- [2,3-d]pyrimidine, m.p. 300 C. (from dimethylformamide), from 2-amino-S-methyl-thiophene-3-carboxylic acid methyl ester and S-nitro-furan-Z-iminocarboxylic acid ethyl ester.

(c) 6-Ethyl-2-(5-nitro-2-furyl) 4 hydroxy-thieno- [2,3-d]pyrimidine, m.p. 271-273 C. (decomp; from dimethylformamide), from S-nitro-furan-Z-iminocarboxylic acid ethyl ester and 5-ethyl-2-amino-thiophene-3-carboxylic acid methyl ester.

(d) 5,6-Dimethyl 2 (5'-nitro-2-furyl)-4-hydroxythieno[2,3-d]pyrimidine, m.p. 300 C. (from dimethylformamide), from 5-nitro-furan-Z-iminocarboxylic acid ethyl ester and 2-amino-4,5-dimethyl-thiophene-3-carboxylic acid methyl ester.

EXAMPLE B 4-'Chloro-2-(5'-nitro-2'-furyl)-thieno [2,3-d] pyrimidine A mixture consisting of 26.3 gm. (0.1 mol) of 2-(5'- nitro-2'-furyl) 4 hydroxy-thien[2,3-d] pyrimidine and 150 ml. of phosphorus oxychloride was refluxed for two hours while stirring. Thereafter, the excess, unreacted phosphorus oxychloride was distilled oil? in vacuo, and the residue. was decomposed with water. The crystalline substance -formed thereby was collected by vacuum filtration, dried and recrystallized from dimethylformamide, yielding 26.5 gm. (94% of theory) of 4-chloro-2-(5'-nitro-2'- furyl)-thieno[2,3-d] pyrimidine, m.p. 245-247 C.

Analysis.C H ClN O S; mol. wt. 281.69: Calculated (percent): C, 42.64; H, 5.01; Cl, 12.49. Found (percent): C, 42.76; H, 5.10; CI, 12.42.

In analogous manner, the following 4-chloro-2-(5' nitro-2'-furyl)-thieno[2,3-d]pyrimidines of the formula II were prepared:

(a) 4-Chloro methyl-2-(5-nitro-2'-furyl)-thieno [2,3-d]pyrimidine, m.p. 220222 C. (from dioxane), from S-methyl 2 (5-nitro-2-furyl)-4-hydroxy-tl1ien [2,3-d]pyrimidine and phosphorus oxychloride.

(b) 4-Chloro 6 methyl-2-(5' nitro-2-fury1)-thieno [2,3-d]pyrimidine, m.p. 194196 C. (from ethanol), from 6-methyl 2 (5'-nitro-2'-furyl)-4-hydroxy-thieno [2,3-d]pyrimidine and phosphorus oxychloride.

' (c) 6-Ethyl-4-chloro-2-(5-nitro-2'-furyl)-thieno[2,3-d] pyrimidine, m.p. 108-109" C. (from ethanol), from 6- 6 ethyl 2 (5'-nitro-2'-furyl)-4-hydroxy-thieno [2,3-d]pyrimidine and phosphorus oxychloride.

(d) 4 Chloro-5,6-dimethyl-2-(5-nitro-2-furyl)-thieno [2,3-d]pyrimidine, m.p. 230-232 C. (from dioxane), from 5,6 dimethyl-2-(5-nitro-2'-furyl)-4-hydroxy-thieno [2,3-d]pyridimine and phosphorus oxychloride.

EXAMPLE C 4-Mercapto-2-(5'-nitro-2'-furyl)-thieno[2,3-d]

pyrimidine A refluxing solution of 2.8 gm. (0.01 mol) of 4-chloro- 2-(5-nitro-2'-furyl)-thieno[2,3-d]pyrimidine in 50 ml. of dimethylformamide was admixed with 9.5 gm. (0.125 mol) of thiourea, and the mixture was allowed to reflux for one minute more. Thereafter, the reaction solution was cooled to room temperature, allowed to stand at room temperature for five minutes, and was then poured into 1 liter of ice water. The crystalline precipitate formed thereby was collected by vacuum filtration, dried and recrystallized from methyl ethyl ketone/ethyl acetate, yielding 1.4 gm. (50% of theory) of 4-mercapto-2-(5-nitro-2'- furyl) thieno[2,3-d]pyrimidine, m.p. 192-193 C. (decomp).

Analysis.C H N O S mol. Wt. 279.30: Calculated (percent): C, 43.00; H, 1.81; N, 15.05. Found (percent): C, 43.20; H, 1.85; N, 15.30.

EXAMPLE D 4-Methylmercapto-2- 5 '-nitro-2-furyl) -thieno [2,3-d] pyrimidine A solution of 1.4 gm. (0.005 mol) of the end product of Example C in 50 ml. of dimethylsulfoxide was admixed at room temperature, and while stirring, first with 0.85 gm. (0.006 mol) of methyl iodide and then gradually with 0.42 gm. (0.006 mol) of potassium methylate, and the resulting mixture was stirred at room temperature for 30 minutes more. Thereafter, the reaction mixture was poured into 0.75 liter of ice water, and the crystalline precipitate formed thereby was collected by vacuum filtration and recrystallized from dimethylformamide, yielding 0.8 gm. (55% of theory) of 4 methylmercapto-2-(5- nitro-2'-furyl)-thieno[2,3-d]pyrimidine, m.p. 264-265 C.

Analysis.-C H N O S mol. wt. 293.33: Calculated (percent): C, 45.05; H, 2.41; N, 14.33. Found (percent): C, 45.00; H, 2.45; N, 14.45.

EXAMPLE E 2-(2-Furyl)-4-hydroxy-thieno [2,3-d]pyrimidine 36.8 gm. (0.2 mol) of ethyl furan-Z-iminocarboxylate and 33.0 gm. (0.21) mol of methyl 2-amino-thiophene-3- carboxylate were dissolved in 150 ml. of xylene, and the solution was heated at C. for 50 hours. Thereafter, the reaction solution was allowed to cool, and the crystalline precipitate formed thereby was collected by vacuum filtration and recrystallized from dioxane in the presence of activated charcoal. 18.2 gm. (42% of theory) of 2-(2'- furyl)-4-hydroxy-thieno[2,3-d] pyrimidine, m.p 242-243 C., were obtained.

Analysis.C H N O S; mol. wt. 218.24: Calculated (percent): C, 55.00; H, 2.77; N, 12.84. Found (percent): C, 55.10; H, 2.81; N, 12.64.

EXAMPLE F 4-Chloro-2-'(2'-furyl)-thieno [2,3-d]pyrimidine A mixture consisting of 21.8 gm. (0.1 mol) of 2-(2'- furyl)-4-hydroxy-thieno[2,3-d]pyrimidine and 75 ml.'of phosphorus oxychloride was refluxed for one hour, whereby everything went into solution. Thereafter, the excess, unreacted phosphorus oxychloride was distilled off in vacuo, and the residue was poured into ice water. The crystalline precipitate formed thereby was collected by vacuum filtration, washed with water and recrystallized from ethanol, yielding 17.1 gm. (72% of theory) of 4- 7 chloro 2 (2'-furyl)-thieno[2,3-d] pyrimidine, m.p. 133- 134 C.

Analysis.-C H ClN OS; mol. wt. 236.70: Calculated (percent): C, 50.75; H, 2.13; N, 11.82. Found (percent): C, 50.63; H, 2.19; N, 11.71.

EXAMPLE G 4-Dibutylamino-2- 2-furyl -thieno 2,3-d] pyrimidine A solution of 4.7 gm. (0.02 mol) of 4-chloro-2-(2'- furyl)-thieno[2,3-d]pyrimidine and 20 ml. of dibutylamine in 75 ml. of ethanol was refluxed for 15 minutes and then poured into water. The aqueous mixture was extracted with methylene chloride, the organic extract was washed with water, dried over sodium sulfate and evaporated in vacuo, and the residue was recrystallized from petroleum ether, yielding 4.3 gm. (65% of theory) of 4- dibutylamino-Z-(2-furyl)-thieno[2,3-d]pyrimidine, m.p. 69-70 C.

Analysis.-C H N OS; mol. wt. 329.47: Calculated (percent): C, 65.61; H, 7.04; N, 12.75. Found (percent): C, 65.70; H, 7.11; N, 12.73.

EXAMPLE H 2( 5 -Bromo-2'- furyl)-4-ch1orothieno [2, 3-d] pyrimidine A small amount of hydroquinone and sulfur were added to a solution of 2.4 gm. (0.01 mol) of 4-chloro-2- (2-furyl)-thieno[2,3-d] pyrimidine in 100 ml. of dichloroethane, and then a solution of 8.0 gm. (0.01 mol) of bromine in 20 ml. of dichloroethane was added dropwise over a period of 30 minutes to the mixture at room temperature, and the resulting mixture was allowed to stand for two hours at room temperature. Thereafter, the reaction mixture was poured into water, the organic phase was separated, and the aqueous phase was extracted once with dichloroethane. The extract solution was combined with the organic phase, the mixed solution was washed once with an aqueous sodium thiosulfate solution and once with water, evaporated in vacuo, and the residue was recrystallized from ethyl acetate, yielding 1.9' gm. (60% of theory) of 2- 5 '-bromo-2-furyl -4-chloro-thieno [2,3-d] pyrimidine, m.p. l94195 C.

Analysis.C H BrClN OS; mol. wt. 313.60: Calculated (percent): C, 38.30; H, 1.29; N, 8.93. Found (percent): C, 38.44; H, 1.41; N, 8.72.

EXAMPLE I 2-(5'-Bromo-2-furyl) -4( B-hydroxyethyl-amino)- thieno [2,3-d1pyrimidine A mixture consisting of 1.6 gm. (0.005 mol) of 2-(5'- bromo-2'-furyl) -4-chloro-thieno [2,3-d] pyrimidine, 5 ml. of 2-amino-ethanol-1 and 20 ml. of ethanol was heated at 60 C. for 15 minutes. Thereafter, the resulting solution was poured over ice, and the precipitate formed thereby was collected by vacuum filtration, washed with water and recrystallized from methyl ethyl ketone, yielding 1.2 gm. (72% of theory) of 2-(5- bromo-2-furyl)-4-( s-hydroxyethyl-amino) thieno[2,3-d]pyrimidine, m.p. 219- 220 C.

Analysis.-C H BrN O S; mol. Wt. 340.22: Calculated (percent): C, 42.37; H, 2.96; N, 12.35. Found (percent): C, 42.50; H, 3.06; N, 12.40.

EXAMPLE I 2-(5'-Carbomethoxy-2'-furyl)-4-hydroxy-thieno- [2, 3-d]pyrimidine 1.8 gm. (0.01 mol) of methyl S-carbomethoxy-fiiran- Z-iminocarboxylate (m.p. 8283 C.; prepared from 5- carbomethoxy-furan-Z-carbonitrile, methanol and hydrochloric acid) and 1.7 gm. (0.11 mol) of methyl 2-aminothiophene 3 carboxylate were intimately admixed with 8 each other, and the mixture was heated at C. for four hours in a round-bottom flask. After some time a crystalline substance began to separate out of the clear molten mass, and at the end of the heating time the contents of the flask had completely solidified. The solid product was triturated with ethanol, and the insoluble matter was collected by vacuum filtration and recrystallized from dimethylformamide, yielding 1.4 gm. (51% of theory) of 2-(5-carbomethoxy-2'-furyl) 4 hydroxythieno[2,3-d] pyrimidine, m.p. 243-245 C.

Analysis.C H N O,,S; mol. wt. 276.28: Calculated (percent): C, 48.90; H, 2.38; N, 16.29. Found (percent): C, 48.79; H, 2.47; N, 16.38.

EXAMPLE K 2-(5'-Carbomethoxy-2'-furyl)-4-chloro-thieno- [2,3-d] pyrimidine A mixture consisting of 2.8 gm. (0.01 mol) of 2-(5"- carbomethoxy-2'-furyl)-4-hydroxy -thieno[2,3-d]pyrimidine and 20 ml. of phosphorus oxychloride was refluxed for 90 minutes, whereby a solution was formed. Thereafter, the excess, unreacted phosphorus oxychloride was distilled off in vacuo, and the residue was poured into ice water. The crystalline precipitate formed thereby was collected by vacuum filtration, dried and recrystallized from a mixture of dimethylformamide and ethanol, yielding 2.6 gm. (89% of theory) of 2-(5-carbomethoxy-2- furyl) 4 chloro thieno[2,3-d1pyrimidine, m.p. 187 C.

Analysis.C H ClN- O S; mol. wt. 294.73: Calculated (percent): C, 48.90; H, 2.38; Cl, 12.03. Found (percent): C, 48.71; H, 2.45; Cl, 12.19.

EXAMPLE L '-Carboxy-2-furyl)-4-dimethylamino-thieno- [2,3-d] pyrimidine A mixture consisting of 1.45 gm. (0.005 mol) of 2 (5 carboxymethyl-2'-furyl)-4-chloro-thieno[2,3-d] pyrimidine and 10 ml. of dimethylamine was heated at 80 C. for one hour in a closed pressure vessel. Thereafter, the excess, unreacted dimethylamine was purged from the vessel, the residual 4-dimethylamino-2-(5-carboxydimethylamido 2' furyl)thieno[2,3-d]pyrimidine was admixed with 10 ml. of concentrated hydrochloric acid, and the mixture was refluxed for two hours. Thereafter, the reaction mixture was cooled and then admixed with an equal volume of water, and the precipitate formed thereby was collected by vacuum filtration, washed with a small amount of water and recrystallized from methanol, yielding 0.7 gm. (48% of theory) of 2-(5-carboxy- 2 furyl) 4 dimethylamino-thieno[2,3-d1pyrimidine, m.p. ZZZ-224 C. (decomp.).

Analysis.C H N O S; mol. wt. 289.32: Calculated (percent): C, 53.97; H, 3.83; N, 14.52. Found (percent):

C, 54.12; H, 3.91; N, 14.44.

Preparation of End Products of the Formula I EXAMPLE 1 4- fiHydroxyethyl-amino) -2- (5 -nitro-2'-furyl) -thieno- [2,3-d] pyrimidine by method A 9. ing.1.72 grn.; (78,% of theory), q f.the compound of the formula a nrg-orr omon ,H' ,N,0,s-, mar. wt. 30(31; Calculated (percent): C, 47.05; H, 3329;' N,"--18.29. Found (percent):

EXAMPLE 2 "refa llbgggas to that described in Examp g 2 ('SGnitrO-T-turyl)-thieno[2,3-d]pyi'imidine, 300 C. (recrystallized from dimethylformamide), of the formula was prepared from 4-chloro-2 ('-nitro-2-furyl)-thieno- [2,3-d]pyrimidine and ammonia.

EXAMPLE 3 Using a procedure analogous to that described in Example 1, 4-methylamino2- (5'-nitro-2'-furyl)-thieno[2,3- d]pyrimidine, m.p. 263-264" C. (recrystallized from di- 499 9 th e V :1 Using; :anproeedureanalogous to that described in Ex ariiplefi 4- 4'-dimethylamino'-2 (5'- -:n-itro-2-furyl thieno- (17C. (recrystallized from 10 [2,3-d]pyrimidine, m.p. 226229 C. (recrystallized from ethanol/dioxane), of the formula Mom was prepared from 4-ch1oro-2-(5'-nitro-2-furyl)-thieno- [2,3-d1pyrimidine and dirnethylamine.

EXAMPLE 8 Using a procedure analogous to that described in Example 1, 4-(di-n-butylamino)-2 (5'-nitro-2'-furyl)- thieno[2,3-d]pyrirnidine, m.p. 102-103 C. (recrystallized from ethanol), was prepared from 4-chloro-2-(5-nitro- 2'furyl)-thieno[2,3-d]pyrimidine and di-n-butylamine.

EXAMPLE 9 Using a procedure analogous to that described in Example 1, 4-(w-hydroxypentyl-amino) 2-(5-nitro-2'- furyl)-thieno[2,3-d1pyrimidine, m.p. 154-155" C. (recrystallized from ethanol), was prepared uirom 4-chloro- 2-(5-nitro-2-furyl) thieno[2,3-d]pyrimidine and 5- amino-pentanol-l.

EXAMPLE 10 Using a procedure analogous to that described in Example 1, 4-(B-hydroxypropyl-amino)-2-(5'-nitro-2-furyl)- thieno[2,3-d]pyrimidine, m.p. 177-178 C. (recrystallized from ethanol), of the formula HN-CHz-CH-CH;

was prepared from 4-chloro-2-(5'-nitro-2'-furyl)-thieno- [2,3-d]pyrimidine and l-amino-propanol-Z.

EXAMPLE 11 Using a procedure analogous to that described in Example 1, 4-[(fi-hydroxy-a-methyl-ethyl)-amino]-2-(5'- nitro-2-furyl)-thieno[2,3-d1pyrimidine, m.p. 244-245 C. (recrystallized from ethanol), of the formula BIL-CH-CHzOH was prepared from- 4-chloro-2-(5'-nitro-2'-furyl)-thieno- [2,3-d]pyrimidine and Z-hydroxy-l-methyl-ethylamine.

EXAMPLE 12 Using a procedure analogous to that described in Example 1, 4-(fiyy-dihydroxypropyl-amino)-2-(5'-nitro- 2'-furyl)-thieno[2,3-d]pyrimidine, m.p. ZZZ-223 C. (recrystallized from ethanol), of the formula I, I A

Hi l CH1 C H-CH; OH

. i1 7 was prepared from 4-chloro-2-(5'-nitro-2'-furyl)-thieno- [2,3-d]pyrimidine and 1-amino-2,3-propanediol.

EXAMPLE 13 Using a procedure analogous to that described in Example 1, 4-(B-methoxyethyl-amino) 2-(5'-nitro-2'- furyl)-thieno[2,3-d]pyrim-idine, mtp. -170-17'1 C. (recrystallized from ethanol), of the formula was prepared from 4 chloro-2-(5-nitro-2-furyl)-thieno- [2,3-d]pyrimidine and p-methoxyethyl-amine.

EXAMPLE 14 Using a procedure analogous to that described in Example 1, 4-(B-ethoxyethyl-amino)-2-(5'-nitro-2-furyl)- thieno[2,3-d]pyrimidine, mp. 131133 C. (recrystallized from ethanol), was prepared from 4-chloro-2-(5'-nitro- 2-furyl) thieno[2,3-d]pyrimidine and ,8 ethoxyethylamine.

EXAMPLE 15 Using a procedure analogous to that described in Example 1, 4 ('y methoxypropyl-amino)-2-(5'-nitro-2- furyl)-thieno[2,3-d]pyrimidine, mp. 151152 C. (recrystallized from ethanol), was prepared from 4-ch1oro- 2-(5'-nitro-2'-fury1)-thieno[2,3-d1pyrimidine and 3 methoxy-amine.

EXAMPLE 16 Using a procedure analogous to that described in Example 1, 4- [N-(fl-hydroxyethyl)-methylamino]-2-(S'-nitro-2'-furyl)-thieno[2,3-d]pyrimidine, mp. 161-162 C. (recrystallized from ethanol), of the formula was prepared from 4 chloro-2-(5'-nitro-2-fury1)-thieno- [2,3-d]pyrimidine and Z-methylamino-ethanol.

EXAMPLE 17 Using a procedure analogous to that described in Example 1, 4-[N(fi-hydroxyethyl)-n-butylamino]-2-(5-nitro-2'-fury1)-thieno[2,3-d]pyrimidine, mp. 132133 C. (recrystallized from ethanol), was prepared from 4- chloro-Z-('-nitro-2'-furyl)-thieno[2,3 d] pyrimidine and 2-(n-butylamino)-ethanol.

EXAMPLE 18 Using a procedure analogous to that described in Example 1, 4- [N- -hydroxypropyl -rnethylamino] -2- 5'-nitro-2'-furyl)-thieno[2,3-d] pyrimidine, mp. 113-115 C. (recrystallized from ethanol), was prepared from 4-chloro- 2-(5-nitro-2-furyl)-thieno[2,3-d]pyrimidine and 3-methylamino-propanol. t

EXAMPLE 19 Using a procedure analogous to that described in Example 1, 4-[N,N-bis-(fl-hydroxyethyl)amino]-2-(5-nitro-2'- r2 furyl)-thieno[2,3-d] pyrimidine, 198-199- C crystallized from ethanol), of the formula l f j r I ll nomo-Ec-N-cm-cmon was prepared from 4-chloro.-2 (5 '-nitro- -f uryl) t hi eno- [2,3-d]pyrimidine and bis-(p-hydroxyethyD-amine;j

EXAMPLE 20 Using a procedure analogous to that described in Ex tro-2'-furyl)-thieno[2,3-d]pyrimidine, mp. 215:2 18" ,,C.

(recrystallized from ethanol), was prepared from-4- chloro-2-( 5 '-nitro-2-furyl)-thieno[2,3-d] pyrimidine and bis-(fl-hydroxypropyD-amine.

EXAMPLE 21 Using a procedure analogous to that described in Example 1, 4- 3 "-hydrogry-piperidino -2- 5'-nitro-2'-furyl thieno [2,3-d] pyrimidine, mp. 178-179 C. (recrystallized from ethanol), of the formula was prepared from 4-chloro-2-(5 -nitro-2 furyl) thieno [2,3-d] pyrimidine and 3-hydro ry-piperidine.

EXAMPLE 22 OaNl" u I o U, I .N'w-f CHI wasv prepared from .4 cliloro g methyl-z-(SinitrQZ-Q furyl)-thieno[2,3-d] pyrimidine and methylaminen EXAMPLE 24 Using a procedure analogous to that described in Example 1, 4-13 hydroxyeth'yl amino) 5methyl-2(5' ni tro-2-furyl) thieno'[2,3-d]pyrimidine; m.p; 211-5 212? C., (recrystallized from methyl ethyl kietone)", was fprepared from 4-chloro 4 5 methyl-2-(5-nitro 2f;fui'yl)gthi{ eno[2,3-d-pyrimidine and 2-an1ino-ethanol.

EXAMPLE- 2 5 Using a procedure analogous ,to that describedv ,in. Example 1, 4-(13. hydroxyethylg:.i'aminOJrG-mQthyI ZrUT I is" nitro-2' furyl) thino[2,'3'-d]pyrimidine, m.p. 170 C. (recrystallized trom e thanol f the formula 1 EXAMPLE 2:; e iUfipg@eprpcedure analogous to that described in Example 1,4 l (B hydroxye tl i yl-alnino) -6-ethyl-2-(5'-n1tro- 2'-furyl) thieno[2,3 d1pyrirnidi ne, m.p. 194-195 C. (recrystallized from ethanonfwasprepared from 4-chloro-6-ethyl 1;; 2. 1 -5 (5,5 nitro-Zffuryl)-thieno[2,3-d]pyrim1- dine and 2-aminoethanol'.

Using a procedure analogous" to that described in Example, 1; 4-'( flfliydroiythyl 'amino) -5,6-dimethyl-2- (5 ni turyn-tnienoras-d] pyrimidine, m.p. 201-202 C.

dioirane) of the formula was prepared from 4-chloro-5,6-dim ethyl-2-(5'-nitro-2'- furyl)-thieno[2,3-d] pyrimidine and Z-amino-ethanol.

v5 M EEXAMPLE 30 4-[(fl-aqctylamino-ethyl) amino] 2- (5'-nitro-2'-furyl)- I hie'ii 3-dj-pyrimidine by method A A solutiori of 1.0 gm. (0.01 mol) of N-acetylethylenediamine in 5 ml. of dimethylsulfoxide was added dropwise to a suspension of' 1.4 (0.005 mol) of 4-chloro- [2,3 d]pyrimidine in 20 ml. of p a up I, 7 ccor'npanied by stirring, and the result ing mixture wasmar tained at that temperature.

for one" hour, whereby a solution wasv formed. Thereafter, the solution was cooled and then poured into water, and the precipitate formed thereby was collected by vacuum filtration, washed with ,wa ter 'and recrystallized from ethanol yielding 0.97 gm.'-;'(56% of theory)'of the compound of the formula 5 14 AnaIysis.C H N O S; mol. wt. 347.36: Calculated (percent: C, 48.41; H, 3.78; N, 20.16. Found (percent): C, 48.50; H, 3.90; N, 20.27.

EXAMPLE 3] Using a procedure analogous to that described in Example 30, 4-[(fl-acetylamino-ethyl) amino]-5-methyl-2- (5-nitro-2-furyl)-thieno[2,3-d]pyrimidine, m.p. 235-- 236 C. (from dimethylformamide), wes prepared from 4-chloro-5-methyl-2-(5'-nitro-2-thieno[2,3 d1pyrimidine and N-acetyl-ethylenediamine.

EXAMPLE 32 Using a procedure analogous to that described in Example 30, 4-[(B-acetylamino-ethyl)amino]-6-methyl-2- (5-nitro-2'-furyl)-thieno[2,3-d]pyrimidine, m.p. 257- 258 C. (from dimethylformamide), was prepared from 4-chloro 6 methyl-2-(5'-nitro-2-furyl)-thieno[2,3-d]pyrimidine and N-acetyl-ethylenediamine.

EXAMPLE 33 Using a procedure analogous to that described in Example 30, 4-[(,B-acetylamino-ethyl)-amino]-5,6-dimethyl- 2-(5'-nitro-2'-furyl)thieno[2,3-d]pyrimidine, m.p. 256- 258 C. (from dimethylformamide), was prepared from 4-chloro-5,6-dimethyl 2 (5'-nitro*2'-furyl)-thieno[2,3- d]pyrimidine and N-acetyl-ethylenediamine.

EXAMPLE 34 4- (fl-Aminoethyl-amino) -2- (5 '-nitro2'-furyl -thieno [2,3-

d]pyrimidine hydrochloride by method A A mixture consisting of 3.5 gm. (0.01 mol) of 4-[(fi' acetylarnino ethyl)-amino]-2-(5'-nitr0-2-furyl)-thieno- [2,3-d] pyrimidine and 25 ml. of concentrated hydrochloric acid was heated for ten hours on a boiling water bath. Thereafter, the resulting reaction solution was evaporated to dryness, and the residue was recrystallized from aqueous ethanol, yielding 1.8 gm. of the compound of the formula 0,: U /N S\. l. U

having a melting point of 283-285 C.

Analysis.C H N O S-HCl; mol. wt. 341.79: Calculated (percent): C, 42.16; H, 3.54; Cl, 10.38. Found (percent): C, 42.20; H, 3.56; Cl, 10.24.

EXAMPLE 35 Using a procedure analogous to that described in Example 34, 4-(fi-aminoethyl-amino)-5-methyl-2-(5'-nitro- 2-furyl)-thieno[2,3 d]pyrimidine hydrochloride, m.p. 290 C. (from aqueous: ethanol), was prepared from 4-[(B-acetylamino-ethyl)-amino]-5-methyl 2 (5'-nitro-. 2'-furyl)-thieno[2,3-d]pyrimidine and concentrated bydrochloric acid.

r EXAMPLE 3.6

Using a procedure analogousto that described in Ex ample '34, 4-(fl-amirioethyl amino)-6-'methyl-2-(5'-riitro 2' furyl)-thieno[2,3-d]pyrimidine hydrochloride, m.p. 300-302 C. (from aqueous ethanol), was prepared trom 4-[(B-acetylamino-ethyl)-amino]-6-methyl 2 (5-n itro- 2'-furyl)-thieno[2,3-d] pyrimidine and.- concentrated bydrochloric acid.

EXAMPLE-37 Using a procedure analogous to that described in Example 34, 4 (B-arninoethyl-ar'nino)-5,6-dimethyl-2-(5'- nitro 2' furyD-thieno[2,3-dlpyrimidine hydrochloride, m.p. 300? C. (from I aqueous ethanol) was prepared from 4 ()S-acet'yla'rnind-ethyl)amino]-5,6 dirnetliyl-2J 15 -nitro-2'-furyl) -thieno [2,3-d] pyrimidine and concentrated hydrochloric acid.

EXAMPLE 38 4-Dibutylamino-2-(5-nitro-2'-furyl)-thieno[2,3-d] pyrimidine by method A of the formula owl J-K T N l I having a melting point of 102-103 C. was obtained.

7 Analysis.C H N.,O S; mol. wt. 374.47: Calculated (percent): C, 57.73; H, 5.92; N, 14.06. Found (percent): C, 57.70; H, 6.00; N, 15.00.

EXAMPLE 39 4-[(fl-Acetoxy-ethyl)-amino]-2-(5'-nitro-2'-furyl)- thieno[2,3-d]pyrimidine by method B 0.2 ml. of concentrated nitric acid was added to a solution of 3.0 gm. (0.01 mol) of 4[(fi-acetoxy-ethyl)- amino]-2-(2'-fury1)-thieno[2,3-d]pyrimidine (m.p. 143-- 145 C., recrystallized from ethyl acetate/hexane) in 30 ml. of acetic acid anhydride at room temperature, the mixture was cooled to -15 C., and then ml. of concentrated sulfuric acid were added dropwise. The reaction mixture was allowed to stand for minutes and was then poured over ice. The resulting aqueous mixture was neutralized (pH 6) with concentrated ammonia while cooling, and the precipitate formed thereby was collected by vacuum filtration and purified by column chromatography on silicagel (particle size 0.2-0.5 mm.), using a mixture of benzene and acetone (8:2) as the flow agent. 0.73 gm. (21% of theory) of the compound of the formula t... prepared tram 4-[(p acetoxy-propyn amim]-2- (2f fuIyD-thierw[2,3-d1pyrimidine and nitric acid.

11 i EXAMPLE. H Using a procedure analogous to thatdescr'ibed'inlEx ample 39, 4- [N- (fl-acetoxy-ethyl )-methylamino] -2- (5 nitro-2-furyl) -thieno [2,3-d] pyrimidine, m.p. 134-13 5 C., of the formula was prepared from 4-[N-(fl-acetoxy-ethyl)-methylamino]- 2-(2'-furyl)-thieno[2,-d]pyrirnidine and 'nitric'acid.

EXAMPLE 42 Using a procedure analogous to that described in- Example 39, 4 acetamino-2-(5'-nitro-2'-furyl)-thieno[2, 3-d]pyrimidine, m.p. 278 -2805(3 of the formula [2,3-d]pyrimidine and nitric acid. 7

EXAMPLE 43 2-(5-Nitro-2'-furyl)-4-propionylaminothieno [2,3-d1pyrimidine by method E; A suspension of 2.6 gm. (0;0-1Zmol) of 4-amino-2- (5'-nitro-2'-furyl)'-thieno[2,3-d]pyrimidine in 20 ml. ,of propionyl chloride was refluxed forI .3 /1 hours, facccim; panied by vigorous stirring. .'l "hereafter ',the reacti p ture was cooled, and thesolid. component was collected by vacuum filtration, washed with methylene chloride and 'with water, dried and recrystallized from tetrahydrofuran, yielding 1.9 gm. (60%- 'of theory) of the compound of the formula was prepared from 4 acetamino 2 (2" furyl) thieno if" s 0 H "5 .HNT'GDT'CHPCHI having a melting point of 215 -217 ..C.

Analysis.C H N O S; mol.

nu oo cmoigl H h was prepared from 4-amino-2-(5t-nitro-2' furyl)-thieno [2,3-d]pyrimidine and chloroacetylchloride.

7 EXAMPLE .43 Using aprocedure analogous"tdthat described in Example 43, 4 dichloroacetamino -"2 5'-.-,nitro'-2'-furyl) -i I i N T was prepared from 4-amino-2-(5'-nitro-2'-furyl)-thieno [2,3-d]pyrimidine and dichloroacetyl chloride.

Thecompounds according to the present invention, that is, those embraced by formula I above and their nontoxic, 'pharmacologically acceptable acid addition salts,-have useful pharmacodynamic properties. More particularly, the compounds of the instant invention exhibit bactericidal, fungicidal and trichomonacidal activities. As bactericides, they are etfective against grampositive as well as gramnegative bacteria, and as trichomonacides they are especially etfectiveagainst trichomonas vaginalis.

The antibacteriaLactivity of the compounds of this invention was ascertained by the agar-dilfusion test and by the series dilution test in close analogy to the test method described by P. Klein in Bakteriologische Grundlagen der Chemotherapeutischen Laboratoriumspraxis, Springer-Verlag, Stuttgart, Germany (1957), pages 53-76 and 87 -409.

{The following compounds, for example, were found to be particularly good .antibacterial agents against Staphylococcus aureus SGS and Streptococcus Aronson even alt-concentrations of as low as less than 'y/mL, and against E. coli even at concentrations as low as less than 25 'y/ml.:;

The following compounds exhibit particularly powerful trichomonaci'dal" action against Trichomonas vaginalis even at concentrationsof as low as less than 0.1 'y/mL:

4-( Bis [B-hydroxyethyH-amino -2- (5'-11itro-2'-furyl) thieno[2,3-d]pyrimidine,. 4- (N [,B-Hydroxyethyl]-methylamino)-2-(5-nitro-2'- 'furyl.) -thieno [2,3-d] pyrimidine,

4- Bis fl-hydroxypropyl] amino -2- (5 '-nitro-2-furyl) thieno[2,3-d]pyrimidine,. and

4,- g-Methoxyethyl-amino) -2- (5 '-nitro-2'-furyl) -thieno [2,3-dl'pyrimidine.

For pharmaceutical purposes the compounds according to 1 the present,v invention are administered to warmblooded "animals topically or'perorally as active ingredients in customary dosage unit compositions, that is, compositions in dosage u'nit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of-' the active ingredient, such astablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective oral dosage unit. 'of the compounds according to the present invention-is'from0166 to 3.33 mgm./kg. body weight, preferably 0.83 to 1.67 mgm./kg. body weight.

The following examples illustrate a few pharmaceutical compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 46 Tablets The tablet composition is compounded from the following ingredients:

Parts 4-Methylamino 2 (5'-nitro 2' furyl)-thieno [2,3-d]pyrirnidine 100.0 Lactose 63.0 Potato starch 50.0 Polyvinylpyrrolidone 5.0 Magnesium stearate 2.0

Total 220.0

EXAMPLE 27 Coated Pills The pill core composition is compounded from the following ingredients:

Parts 4 Methylamino 2 (5'-nitro-2'-furyl)-thieno[2,

3-d]pyrimidine 50.0 Lactose 30.0 Corn starch 30.0 Gelatin 3.0 Cellulose, microcrystalline 6.0 Magnesium stearate 1.0

Total 120.0

Preparation: The thienopyrimidine compound is intimately admixed with the lactose and the corn starch, the mixture is moistened with an aqueous 12% solution of the gelatin, the moist mass is forced through a 1.5 mm.- mesh screen, and the resulting granulate is dried at 45 C. and again passed through a 1.0 mm.-mesh screen. The dry granulate is admixed with the cellulose and the magnesium stearate, and the composition is compressed into mgm.-pill cores, which are subsequently coated in conventional manner with a thin shell consisting essentially of a mixture of talcum and sugar and finally polished with beeswax. Each coated pill containsSO mgm. of the thienopyrimidine compound and is an oral dosage unit composition with effective antibacterial action.

EXAMPLE 48 inal Tablets The tablet composition is compounded from the follow. ing ingredients: a

Preparation: The thienopyrimidine compound is intimately admixed with the sorbitol and the carboxymethyl cellulose, the mixture is moistened with aqueous 50% ethanol (150 gm. per 1000 tablets), the moist mass is forced through a 2 mm.-mesh screen, the resulting granulate is dried at 45 C. and again passed through the screen, the dry granulate is admixed with the magnesium stearate, and the composition is compressed in conventional manner into 1000 mgm.-vaginal tablets. Each tablet contains 100 mgm. of the thieno-pyrimidine compound and is a dosage unit composition with effective trichomonacidal action against Trichomonas vaginalis.

EXAMPLE 49 Tincture The tincture is compounded from the following ingredients:

Parts 4 (fi-Aminoethyl-amino) 2 -(5-nitro-2'-furyl)- thieno[2,3-d]pyrimidine 1.0 Polyethyleneglycol 400 99.0

Total 100.0

Preparation: The thienopyrimidine compound is dissolved in the polyethyleneglycol by warming, and the solution is cooled and filtered. The filtrate contains 1% by weight of the thienopyrimidine compound an is a topical composition with eflective antibacterial action.

EXAMPLE 50 Lotion The lotion is compounded from the following ingredients:

Parts 4 Ethylamino 2-(5'-nitro-2-furyl)-thieno[2,3-d]

pyrimidine 1.0 Sorbitan monopalmitate (Span 40) 1.0

Long-chain, high-molecular-weight polyglycolether,

water-soluble (Cremophor O) 2.0 Cetyl stearyl alcohol (Lanette O) 2.0 Spermaceti 1.0 Decyl oleate 5.0 Parafiin oil 1.0 Distilled water 87.0

Total 100.0

Coated pills with combination of active ingredients I The pill core composition is compounded from the following ingredients:

Parts 4 (B Hydroxyethyl-amino)-2-(5'-nitro-2'-furyl)- v thieno[2,3-d]pyrimidine 50.0 Papaverine 25.0 Corn starch 32.0

Gelatin 3.0 Cellulose, microcrystalline 9.0 Magnesium stearate 1.0..

Total 120.0

The pills are compounded and manufactured in the same way as in Example 47. Each coated pill contains 50 mgm.

of the thienopyrimidine compound and 25 mgm. of papaverine and is an oral dosage unit composition with effective antibacterial and smooth muscle relaxing actions.

EXAMPLE 52 Gelatin capsules The capsule filler composition is compounded from the following ingredients:

Parts 4 [Bis(/3 hydroxy-ethyl)amino]-2-(5'-nitro-2- furyl)-thieno[2,3-d]pyrimidine 150.0 Lactose 100.0 Talcum ..50.0

Total 300.0

Preparation: The ingredients are intimately" admixed with each other, the mixture is passed through 'a 1.0 mm; mesh screen, and 300 mgm.-portions of the resulting com? position are filled into gelatin capsules of suitable size. Each capsule contains mgm. of the thienopyrimidine compound and is an oral dosage unit composition with effective antibacterial and trichomonacidal action.

Analogous results are obtained when anyone of'the other thienopyrimidines embraced by formula I or a' nontoxic acid addition salt thereof is substituted for the particular thienopyrimidine in Examples 46 through '52.'Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range or concentration set forth above,.and the amounts and nature of the inert pharmaceutical carrier ingredientsmay be varied to meet particular requirements. Y

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art-that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims. We claim:

1. A compound of the formula amino ethyl-amino; acetaminoethyl-amino; 'acetoxy-- (alkylene of 2 to 3 carbon atoms)-amino; N-acetoiryethyl-methylamino; or hydroxy-piperidino; and R and R are each hydrogen, methyl or ethyl,

or a non-toxic, pharmacologically acceptable acid addition" salt thereof.

2. A compound according-to claiml, which is 4-methylamino 2-(5'-nitro-2'-fury1)-thieno[2,3-d]pyrimidine or a.

non-toxic, pharmacologically acceptable acid addition salt thereof. 1

3. A compound according to claim 1, which is 4-ethy1 amino 2-(5'-nitro-2'-furyl)-thieno[2,3-d] pyrimidine ora non-toxic, pharmacologically acceptable acid addition salt thereof.

4. A compound according to claim 1, which, propylamino-Z- 5 -nitro- 2-furyl -thieno [2, 3-d ]-pyrimidine pharmacologically acceptable acid addition;

or a non-toxic, salt thereof.

5. A compound according to claim 1, which is 4-(5- hydroXyethyl-amino) 2-(5' nitro-2'-furyl)thieno[2,3-d] pyrimidine or a non-toxic, pharmacologically acceptable acid addition salt thereof.

6. A compound according to claim 1, which is 4-(fi,'ydihydroXypropyl-amino -2- 5-nitro-2'-furyl -thieno 2,3- d]pyrimidine or a non-toxic, pharmacologically acceptable acid addition salt thereof.

7. A compound according to claim 1, which is 4-(5- methoxyethyl-amino) 2-(5'-nitro-2-furyl)-thieno[2,3-d] pyrimidine or a non-toxic, pharmacologically acceptable acid addition salt thereof.

8. A compound according to claim 1, which is 4-(,8- aminoethyl-amino) 2 -(5'-nitro-2-furyl)-thieno[2,3-d] pyrimidine or a non-toxic, pharmacologically acceptable acid addition salt thereof.

9. A compound according to claim 1, which is 4-[bis- (5 hydroxyethyl)-amino]-2-(5'-nitro-2-furyl)-thien0[2, 3-d] pyrimidine or a non-toxic, pharmacologically acceptablc acid addition salt thereof.

10. A compound according to claim 1, which is 4-[N- (B hydroxyethyl)-methyl-amino] 2 (5'-nitro-2'-furyl)- thieno[2,3-d]pyrimidine or a non-toxic, pharmacologically acceptable acid addition salt thereof.

11. A compound according to claim 1, which is 4-[bis- (B hydroxypropyD-amino] 2-(5'-nitro-2'-furyl)-thieno [2,3-d] pyrimidine or a non-toxic, pharmacologically acceptable acid addition salt thereof.

References Cited UNITED STATES PATENTS 3,661,908 5/1972 Woitun et al. 260--256.5 R

DONALD G. DAUS, Primary Examiner R. D. MCCLOUD, Assistant Examiner US. Cl. X.R.

" UNITED STATES PATENT OFFICE ..(s/sa) CERTIFICATE OF CORRECTION Pltlnt N0. 3,8301813 Dated August 201 EBERHARD womm, WOLFGANG REU'IER Inventofls) It is certified that error appears in the aboveidentified patent ,and that said Letters Patent are hereby corrected as shown below:

F230]. 1 line a, "woitum" should read: woitun 1 Col. 3 "line 1," "hdroxyl' should read hydroxyl Col. 11 line 36, "B-methdxy-l' should read: 3-methoxirpropyl- Col. 12 line 6-7, "l, l-/8-hydroxyethyl" should read:

lfll-(B-hydroxyethyl C01. 1 1 line 8, "wes should read was Col. 1a line 10, "-2-(5-n1tro-2'-th1eno[2,3-

should read:

- -2(5Lnitro-2 '-fury1)--thieno[2,3-

Col. 16 line 16, -th1eno[2, -d] should read: I

-thieno[2,3-dj Col. 20 line 52," "alkyl of 1 to 5'" should read;

I (alkyl of l to 5 i Col; 20 line 58, "f-amino-ethyl-rhino" should read:

- )-am1no;" ailino-ethyl-amino Signed and sealed this 29th day of October 1974.

(SEAL) fittest:

MCCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents 

